Lysosomal storage diseases are a class of metabolic disorders caused by mutations in proteins important for lysosomal function. There are many types of lysosomal storage diseases, and although each is relatively rare, their combined prevalence is estimated to be 1 in 8,000 live births1. Juvenile neuronal ceroid lipofuscinosis (JNCL or Juvenile Batten disease) is a fatal, neurodegenerative lysosomal storage disease that typically presents in children between the ages of 5-10 years, initiating as blindness and progressing to seizures, motor loss, and subsequent cognitive decline2. Juvenile Batten Disease is caused by an autosomal recessive mutation in the CLN3 gene, most commonly due to a 1 kb deletion in exons 7 and 83, and although the protein has been shown to reside in lysosomal membranes and other membrane compartments, its function remains elusive. Juvenile Batten Disease is characterized by the abnormal intracellular accumulation of lipid and protein (ceroid lipofuscin) in lysosomes, resulting in the development of insoluble inclusions. Although lysosomal inclusions form in all cell types in the body, neurons are the most sensitive and undergo progressive cell death2. The seriousness of this neuronal cell death is magnified by the fact that the central nervous system (CNS) is not capable of regeneration. Currently, there is no treatment for Juvenile Batten Disease, which is uniformly fatal and associated with a decreased life expectancy into the late teens or early twenties.
Microglia play a role in initiating inflammatory events immediately following CNS bacterial infection or insult. In particular, the inflammasome has been defined as a key molecular pathway responsible for processing the proinflammatory cytokine interleukin-1 beta (IL-1β) into its active form in microglia8. Depending on the initiating stimulus, activated microglia also produce reactive oxygen species (ROS)9,10, which have recently been shown to trigger inflammasome activation11, linking the two processes. Studies have revealed oxidative imbalance in the brains of CLN3 knockout mice12 and increased sensitivity of CLN3 mutant Drosophila to oxidative stress13. Further, IL-1β has long been recognized for its neurotoxic properties6,14. Collectively, these observations indicate that these pathways intersect and provide a pathological target following CLN3 mutation.
Mass spectrometry studies of samples from the brains of JNCL patients have identified several perturbations in the CNS metabolome7. In particular, the disease is associated with elevated glutamate levels, which is thought to contribute to neuronal excitotoxicity. Astrocytes play a major role in maintaining glutamate concentrations through glutamate transporters and gap junction communication (GJC)8.
Astrocytes form syncytial networks within the CNS through GJC to influence expansive parenchymal domains. Gap junctions (GJs) are formed by the joining of two hemi-channels (HCs) between adjacent cells each composed of six connexin (Cx) subunits1. Astrocytic GJs are capable of transmitting a wide variety of small molecules (<1 kDa), including glutamate, ATP, glucose, Ca2+, K+, and Na2+ and, as such, play a vital role in maintaining ionic and metabolic stability in the CNS parenchyma. In contrast, astrocyte HCs allow the direct communication between the intra- and extracellular milieus and can be formed by two distinct families, namely Cxs and pannexins (Panx)2.
Numerous neurodegenerative diseases, including JNCL, are typified by an inflammatory component and our recent studies have revealed that primary microglia from CLN3Δex7/8 mice are inappropriately primed to secrete elevated levels of numerous proinflammatory mediators following exposure to C6 ceramide and neuronal lysates, two stimuli that are elevated in the brains of JNCL patients3,4, whereas wild type microglia are relatively non-responsive38.
Unfortunately, our understanding of the etiology of this devastating disease is limited. Therefore, a need exists in the art for prophylactic and therapeutic methods for individuals diagnosed with Juvenile Neuronal Ceroid Lipofuscinosis or Juvenile Batten Disease. A need also exists for the prophylactics and therapeutics used in those methods.